With the onset of cancers which are refractory to most conventional treatments, there is a need for new and effective chemotherapeutics. As details emerge about the molecular etiology of various cancers, new chemotherapeutics can be designed which affect one or more vulnerable targets associated with a given cancer at a sub-cellular level.
Certain cancers (and indeed other diseases of abnormal cellular growth) include those which are due to the dysregulation of one particular molecular signaling pathway in the body. Restoring regulation of that particular pathway to normal or near-normal levels can have a positive impact in treating the patient, including a reduction in tumor size or even putting the patient into remission.
For example, perturbations of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway are closely associated with the etiology of most solid tumors. The PI3K/AKT/mTOR pathway can be overactivated by a number of molecular effectors, including chemokines, the loss of inositol polyphosphate-4-phosphatase type II (INPP4B) or phosphatase and tensin homolog (PTEN) expression, or by mutations in PI3K itself. Overactivation of this pathway can manifest in a number of molecular and morphological changes which are characteristic of tumorigenesis, including increased cell proliferation, survival and motility, and altered cell cycle entry. mTOR is a central regulator of cell growth which acts by controlling cellular protein translation. Several small molecules have been described as being mTOR inhibitors which are useful for treating cancers. PI3K is a heterodimeric enzyme that generates lipid second messengers, such as phosphatidylinositol-3,4,5-triphosphate (PIP3), that mediate signal transduction. PI3K enzymes regulate key signal transduction pathways controlling vital cell processes that are implicated in carcinogenesis, and include four isoforms; i.e., p110α, p110β, p110δ and p110γ. Specific mutations in p110α have been identified in various cancers. Several small molecules have been described as inhibitors of PI3K. Further, there are a number of compounds, including wortmannins and rapamycins, which have been shown to be highly potent and specific inhibitors of PI3K and mTOR, respectively.
Indeed, several recent compounds have been described as being useful in regulating the PI3K/mTOR pathway. For example, GDC-0941, PX-866, XL-147, BKM-120, and BAY 80-6946 are inhibitors of PI3K, whereas rapamycin, temsirolimus (CCI-779), everolimius (RAD001), deforolimus (AP23573), OSI-027 and AZD8055 are inhibitors of mTOR. However, intervention at a single point in a the PI3K/AKT/mTOR signaling pathway may not be as effective in treating solid tumors as targeting multiple pathway members. Administering multiple drugs to a cancer patient, each of which inhibit a certain target in the PI3K or mTOR pathway, carries its own risks in terms of increased drug load, potential toxicity, drug-drug interactions and the like. What remains in the art, therefore, is the need for single compounds which regulate the PI3K/AKT/mTOR pathway by targeting both PI3K and mTOR. Certain compounds recently described in the art, including BEZ-235, XL-765, GSK-2126458, PKI-587 (PF-05212384), PF-04691502, and GDC-0980 have been reported to target both PI3K and mTOR. However, the need remains for compounds with this type of dual activity profile to be developed and approved for clinical use.